US20080160586A1 - Process for the Purification of Tacrolimus - Google Patents
Process for the Purification of Tacrolimus Download PDFInfo
- Publication number
- US20080160586A1 US20080160586A1 US11/718,415 US71841505A US2008160586A1 US 20080160586 A1 US20080160586 A1 US 20080160586A1 US 71841505 A US71841505 A US 71841505A US 2008160586 A1 US2008160586 A1 US 2008160586A1
- Authority
- US
- United States
- Prior art keywords
- tacrolimus
- purification
- silver
- acetone
- silica gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- QJJXYPPXXYFBGM-FKLMXRLUSA-N C=CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC Chemical compound C=CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC QJJXYPPXXYFBGM-FKLMXRLUSA-N 0.000 description 3
- 0 *C.CCC(C)C.CCC(CC(C)C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound *C.CCC(C)C.CCC(CC(C)C1=CC=CC=C1)C1=CC=CC=C1 0.000 description 1
- UQRSHGABDAWKBG-LGWQIUMFSA-N C=CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC.C[Ag] Chemical compound C=CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC.C[Ag] UQRSHGABDAWKBG-LGWQIUMFSA-N 0.000 description 1
- RQYGKZGKXDOUEO-FKLMXRLUSA-N CCC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC Chemical compound CCC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC RQYGKZGKXDOUEO-FKLMXRLUSA-N 0.000 description 1
- IMWJLLUSKJLPRG-IWPCUREPSA-N CCC[C@H](/C=C(\C)/C[C@@H](C)C[C@@H]([C@H]([C@H](C[C@H]1C)OC)O[C@]1(C(C(N(CCCC1)C1C(O[C@@H]([C@H](C)[C@H](C1)O)/C(/C)=C/[C@H](CC[C@H]2O)C[C@H]2OC)=O)=O)=O)O)O)C1=O Chemical compound CCC[C@H](/C=C(\C)/C[C@@H](C)C[C@@H]([C@H]([C@H](C[C@H]1C)OC)O[C@]1(C(C(N(CCCC1)C1C(O[C@@H]([C@H](C)[C@H](C1)O)/C(/C)=C/[C@H](CC[C@H]2O)C[C@H]2OC)=O)=O)=O)O)O)C1=O IMWJLLUSKJLPRG-IWPCUREPSA-N 0.000 description 1
- ZDQSOHOQTUFQEM-JYWMKRLESA-N CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC Chemical compound CC[C@@H]1/C=C(\C)C[C@@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCCC3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC ZDQSOHOQTUFQEM-JYWMKRLESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/32—Bonded phase chromatography
- B01D15/322—Normal bonded phase
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/32—Bonded phase chromatography
- B01D15/325—Reversed phase
Definitions
- the present invention relates in general to pharmacologically active immunosuppressant and antimicrobial tricyclic macrolides, in particular to a process for the recovery and purification of Tacrolimus (I)
- Tacrolimus (I) (17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxy-4-azatricyclo-[22.3.1.0 4.9 ]octacos-18-en-2,3,10,16-tetraone
- EP 0184162 discloses a process for the preparation of Tacrolimus and derivatives thereof through fermentation and chemical synthesis.
- fermentation with Streptomyces sp. produces, further to Tacrolimus, also the 17-ethyl-derivative (II) (17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxi-4-azatricylo-[22.3.1.0 4.9 ]octacos-18-ene-2,3,10,16-tetraone), commonly known as FK520
- EP 0184162 also discloses methods for its extraction, purification and recovery.
- the recovery of the products from fermentation broths is achieved by means of known extraction techniques, such as: use of conventional solvents to extract the activity from the broth or micelium; absorption/elution with ion-exchange anionic and cationic resins and non-ionic adsorbent resins; purification on conventional chromatographic supports such as silica gel, alumina and cellulose; decolourization with active charcoal, crystallization and recrystallization.
- U.S. Pat. No. 6,492,513 teaches to purify Tacrolimus from impurities (II) and (III) by ion-exchange cationic resins pretreated with silver salts (in particular silver nitrate).
- silver salts in particular silver nitrate.
- the use of silver salts for the separation of cis-trans isomers of unsaturated aliphatic acids with the same carbon atoms number is known in the literature (J. Chromatography, 149 (1978) 417).
- Silver salts form ⁇ -complexes with unsaturated compounds which are therefore separated according to their conformation.
- 6,492,513 allows to separate Tacrolimus (which has a 17-allyl side chain) from the two impurities with 17-saturated side chains, since Tacrolimus is more retained than the other two impurities on cationic ion-exchange resins, due to the formation of the silver complex.
- R is a hydrogen or a halogen atom.
- Tacrolimus can be conveniently purified from degradation impurities as silver complex (IV)
- the process of the invention comprises the dissolution of the fermentation product of Streptomyces sp in a water/organic solvent mixture containing silver ions and elution of the solution on a C18 reverse phase silica gel column.
- Silver ions are released in the solution from silver salts, preferably silver nitrate or perchlorate.
- concentration of silver ions preferably ranges from 0.05 to 1.30 mol/l, more preferably from 0.20 to 0.30 mol/l.
- the organic solvent of the solvent mixture in which the product to purify is dissolved is an organic solvent wherein Tacrolimus is soluble, preferably selected from acetone, methanol and acetonitrile.
- the amount of C18 reverse phase silica is 8 times the weight of crude product, preferably 12-14 times. Elution of the ⁇ -complex Tacrolimus-silver is carried out with the same solvent mixture used for the dissolution, gradually increasing the amount of organic solvent and collecting proper fractions from the chromatographic column. The concentration of silver ions in the eluent will range from 0.05 mol/l to 1.30 mol/l.
- the reverse phase silica is C18 silica with different granulometry, preferably 5-15 ⁇ m and 70-230 ⁇ m.
- the analytical method for the analysis of the eluted fractions is that disclosed in the literature (Y. Namiki et al. Cromatographia Vol. 40, No 5/6 March 1995) whereby it is possible to identify, by calculating the RRT, impurities (II), (III) and other degradation impurities.
- the process of the invention can also comprise chromatographic purification on a non ionic resin and chromatographic purification on normal-phase silica gel, for example according to EP 0184162. These purification steps can be carried out either before or after the purification on C18 reverse phase silica gel. According to a particularly preferred embodiment, these further purifications can be carried out before, as hereinafter described in greater detail.
- the fermentation broth or mycelium is extracted with organic solvents wherein Tacrolimus is soluble, for example ketones or alcohols, preferably acetone and methanol; the extraction product is subjected to adsorption chromatography on non ionic adsorbing resin, then to normal phase silica gel chromatography to purify Tacrolimus, impurities (II) and (III) and degradation products from other compounds deriving from the fermentation broth (substances produced by the microorganism, inorganic salts and substances deriving from starting materials).
- organic solvents wherein Tacrolimus is soluble for example ketones or alcohols, preferably acetone and methanol
- the extraction product is subjected to adsorption chromatography on non ionic adsorbing resin, then to normal phase silica gel chromatography to purify Tacrolimus, impurities (II) and (III) and degradation products from other compounds deriving from the fermentation broth (substances produced by the microorganism, inorgan
- the resulting product is dissolved in an aqueous-organic solution and eluted on C18 reverse phase silica gel to recover the ⁇ -complex Tacrolimus-silver (IV), which is extracted with organic solvents in which Tacrolimus is soluble, for example ethyl acetate.
- the extraction product is concentrated and crystallized with known methods.
- adsorbent resins available on the market, preferably those manufactured by Mitsubishi Chemical Corporation (series SP200 o SP800) or Rohm and Haas (series XAD).
- Preferred solvents are ketones or alcohols, more preferred are acetone and methanol.
- the solvents are preferably alkanes, esters, ketones and alcohols, more preferably n-hexane and ethyl acetate.
- Extraction and crystallization are carried out according to the procedures for solvent extraction and recovery of Tacrolimus disclosed in the literature.
- the solution containing the purified ⁇ -complex Tacrolimus-silver is concentrated under vacuum to remove the organic solvent and subsequently extracted with 0.5-3 volumes of organic solvent, preferably ethyl acetate.
- the organic phase is washed with 1 volume of deionized water for 2-3 times and subsequently concentrated to small volume.
- Tacrolimus precipitates as monohydrate crystals by addition of deionized water.
- the resulting crystals are characterized by high purity (HPLC area %>99% according to the HPLC method reported in Y. Namiki et al. Chromatographia Vol. 40, No 5/6 March 1995).
- the process of the invention is particularly advantageous over known processes in terms of productivity, selectivity of the separation of the impurities and quality of the finished product.
- productivity the process of the invention requires an amount of chromatographic carrier (C18 reverse phase silica) per unit of crude product markedly lower (about 5-8 times) than that disclosed in U.S. Pat. No. 6,576,135 (wherein the chromatographic carrier is HP20ss).
- the percentage weight ratio of crude product to C18 reverse phase silica is 5-8%, while in the process of U.S. Pat. No. 6,576,135 the percentage ratio of crude product to chromatographic carrier HP20ss is 1%.
- the higher amount of product per weight unit of chromatographic carrier allows remarkable improvements in terms of productivity and costs on an industrial scale.
- the amount of finished product being the same the volumes in the purification phase are reduced by 5-8 times and as a consequence the costs due to silver salts (in particular AgNO 3 ) are also reduced.
- the oily phase is added with 180 g of silica gel (0.063-0.200 mm Merck) and 180 ml of ethyl acetate.
- the mixture is stirred and subsequently evaporated to a powder, which is loaded onto a column containing 1 litre of silica gel (0.063-0.200 mm Merck) in n-hexane. Purification is accomplished eluting with 4 liters of n-hexane, then 4 litres of 75/25 n-hexane/ ethyl acetate and finally 10 litres of ethyl acetate.
- the eluted fractions are collected and each of them is analyzed by HPLC on a C18 column with water/acetonitrile as the eluant.
- Activity-enriched fractions are pooled and concentrated to obtain a white-yellowish solid (12 g).
- the solid of example 2 (12 g, containing 8.5 g of Tacrolimus), is dissolved in 400 ml of a 50/50 water/acetone solution containing 30 g of AgNO 3 .
- the solution is passed through 200 ml of C18 reverse phase silica 15 ⁇ m (manufactured by Grace-Amicon).
- the column is eluted with 1000 ml of a 50/50 water/acetone solution containing 51 g of AgNO 3 and finally with 250 ml of a 20/80 water/acetone solution.
- the eluate is divided into fractions which are analyzed according to the analytical method reported in the Y. Namiki et al. Chromatographia Vol. 40, No 5/6 March 1995.
- the following table reports the variation of the Tacrolimus concentration and of the impurities during the various purification steps on C18 reverse phase silica.
- the solution obtained according to example 3 is added with 700 ml acetonitrile. 1200 ml deionized water is slowly added (1-2 hours) at a temperature of 25° C. and the solution is cooled to 5° C., then allowed to stand at this temperature for 12-14 hours. After filtration 7.0 g Tacrolimus is obtained with high purity (HPLC Area %>99%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Transplantation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2004A002098 | 2004-11-03 | ||
IT002098A ITMI20042098A1 (it) | 2004-11-03 | 2004-11-03 | Processo per la purificazione di tacrolimus |
PCT/EP2005/011393 WO2006048145A1 (en) | 2004-11-03 | 2005-10-24 | Process for the purification of tacrolimus |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080160586A1 true US20080160586A1 (en) | 2008-07-03 |
Family
ID=35542958
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/718,415 Abandoned US20080160586A1 (en) | 2004-11-03 | 2005-10-24 | Process for the Purification of Tacrolimus |
Country Status (8)
Country | Link |
---|---|
US (1) | US20080160586A1 (ja) |
EP (1) | EP1812447A1 (ja) |
JP (1) | JP2008518984A (ja) |
KR (1) | KR20070083930A (ja) |
CN (1) | CN101048415A (ja) |
CA (1) | CA2586193A1 (ja) |
IT (1) | ITMI20042098A1 (ja) |
WO (1) | WO2006048145A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012026665A1 (en) * | 2010-08-24 | 2012-03-01 | Ewha University - Industry Collaboration Foundation | Novel tacrolimus derivatives, a neuroprotective composition comprising the same, an immunosuppressive composition comprising the same, a method for preparing the same, and a mutant for producing the same |
US9505779B2 (en) | 2010-08-24 | 2016-11-29 | Intron Biotechnology, Inc. | Tacrolimus analogues, a neuroprotective composition comprising the same, an immunosuppressive composition comprising the same, a method for preparing the same, and a mutant for producing the same |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007013017A1 (en) * | 2005-07-29 | 2007-02-01 | Ranbaxy Laboratories Limited | A process for purification of macrolides |
ITMI20051549A1 (it) * | 2005-08-05 | 2007-02-06 | Antibioticos Spa | Purificazione del tacrolimus su supporti dimorigine vegetale |
KR100891313B1 (ko) * | 2007-08-17 | 2009-03-31 | (주) 제노텍 | 담체로 작용하는 흡착성 수지의 제공에 의한 트리사이클로화합물의 생산 및 추출 방법 |
KR101033845B1 (ko) * | 2008-09-18 | 2011-05-16 | (주) 제노텍 | 은 이온 용액 결정화에 의한 불포화 알킬기를 가진 락톤 화합물 정제방법 |
CN101712685B (zh) * | 2009-06-22 | 2012-07-04 | 鲁南制药集团股份有限公司 | 一种他克莫司粗品的精制方法 |
IN2014DN09575A (ja) * | 2012-05-23 | 2015-07-17 | Lanzatech New Zealand Ltd | |
CN107556327A (zh) * | 2017-10-31 | 2018-01-09 | 无锡福祈制药有限公司 | 一种分离纯化他克莫司的方法 |
KR102645011B1 (ko) | 2023-10-17 | 2024-03-07 | 주식회사 라이프슈티컬 | 고상 추출법을 이용한 타크롤리무스의 정제방법 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6492513B1 (en) * | 1999-05-25 | 2002-12-10 | Fujisawa Pharmaceutical Co., Ltd. | Method for separating analogous organic compounds |
US7473366B2 (en) * | 2003-12-05 | 2009-01-06 | Biocon Limited | Process for the purification of macrolides |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8430455D0 (en) * | 1984-12-03 | 1985-01-09 | Fujisawa Pharmaceutical Co | Fr-900506 substance |
US4894366A (en) * | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
CA2018710A1 (en) * | 1989-06-13 | 1990-12-13 | Shieh-Shung T. Chen | L-683,590 microbial transformation product |
JPH03275689A (ja) * | 1990-03-23 | 1991-12-06 | Fujisawa Pharmaceut Co Ltd | Fr900506物質の脱メチル体およびヒドロキシ体 |
JP3067183B2 (ja) * | 1990-09-18 | 2000-07-17 | 藤沢薬品工業株式会社 | Fr900506物質の製造法 |
EP0480623A1 (en) * | 1990-10-11 | 1992-04-15 | Merck & Co. Inc. | New halomacrolides and derivatives having immunosuppressive activity |
US5194378A (en) * | 1991-01-28 | 1993-03-16 | Merck & Co., Inc. | Process for producing fk-506 |
TW553946B (en) * | 1999-09-08 | 2003-09-21 | Fujisawa Pharmaceutical Co | Method for separating lactone-containing high-molecular weight compounds |
EP1756290B1 (en) * | 2004-04-12 | 2016-05-04 | Biocon Limited | Streptomyces sp. bicc 7522 and its use for the production of macrolides |
-
2004
- 2004-11-03 IT IT002098A patent/ITMI20042098A1/it unknown
-
2005
- 2005-10-24 JP JP2007539497A patent/JP2008518984A/ja active Pending
- 2005-10-24 EP EP05807586A patent/EP1812447A1/en not_active Withdrawn
- 2005-10-24 US US11/718,415 patent/US20080160586A1/en not_active Abandoned
- 2005-10-24 KR KR1020077010048A patent/KR20070083930A/ko not_active Application Discontinuation
- 2005-10-24 WO PCT/EP2005/011393 patent/WO2006048145A1/en active Application Filing
- 2005-10-24 CN CNA2005800370313A patent/CN101048415A/zh active Pending
- 2005-10-24 CA CA002586193A patent/CA2586193A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6492513B1 (en) * | 1999-05-25 | 2002-12-10 | Fujisawa Pharmaceutical Co., Ltd. | Method for separating analogous organic compounds |
US7473366B2 (en) * | 2003-12-05 | 2009-01-06 | Biocon Limited | Process for the purification of macrolides |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012026665A1 (en) * | 2010-08-24 | 2012-03-01 | Ewha University - Industry Collaboration Foundation | Novel tacrolimus derivatives, a neuroprotective composition comprising the same, an immunosuppressive composition comprising the same, a method for preparing the same, and a mutant for producing the same |
US9505779B2 (en) | 2010-08-24 | 2016-11-29 | Intron Biotechnology, Inc. | Tacrolimus analogues, a neuroprotective composition comprising the same, an immunosuppressive composition comprising the same, a method for preparing the same, and a mutant for producing the same |
Also Published As
Publication number | Publication date |
---|---|
ITMI20042098A1 (it) | 2005-02-03 |
JP2008518984A (ja) | 2008-06-05 |
CN101048415A (zh) | 2007-10-03 |
EP1812447A1 (en) | 2007-08-01 |
CA2586193A1 (en) | 2006-05-11 |
KR20070083930A (ko) | 2007-08-24 |
WO2006048145A1 (en) | 2006-05-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080160586A1 (en) | Process for the Purification of Tacrolimus | |
US8362238B2 (en) | Method for refining of high purity of tacrolimus | |
US20070117976A1 (en) | Method of purifying macrolides | |
EP1697383B1 (en) | Process for the purification of tacrolimus | |
US20080000834A1 (en) | Process for purifying Tacrolimus | |
US20080161555A1 (en) | Purification of Tacrolimus on Supports of Vegetable Origin | |
US20060142565A1 (en) | Method of purifying tacrolimus | |
EP1896488B1 (en) | Process for purifying tacrolimus | |
WO2007013017A1 (en) | A process for purification of macrolides | |
KR101033845B1 (ko) | 은 이온 용액 결정화에 의한 불포화 알킬기를 가진 락톤 화합물 정제방법 | |
US8193345B2 (en) | Purification method of lactone compounds containing unsaturated alkyl group by extraction with silver ion solution | |
WO2008059516A2 (en) | Process for purification of macrolides |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ANTIBIOTICOS S.P.A., ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CABRI, WALTER;PAISSONI, PAOLO;ROLETTO, JACOPO;AND OTHERS;REEL/FRAME:019736/0026 Effective date: 20070426 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |